Rare catastrophes and evolutionary legacies: human germline gene variants in MLKL and the necroptosis signalling pathway

Abstract

Programmed cell death has long been characterised as a key player in the development of human disease. Necroptosis is a lytic form of programmed cell death that is universally mediated by the effector protein mixed lineage kinase domain-like (MLKL), a pseudokinase. MLKL's activating kinase, receptor interacting protein kinase 3 (RIPK3), is itself activated within context specific scaffolds of receptor interacting protein kinase 1 (RIPK1), Z-DNA Binding Protein-1 (ZBP1) or TIR domain-containing adaptor inducing interferon-β (TRIF). These core necroptosis modulating proteins have been comprehensively revealed as potent drivers and suppressors of disease in inbred mouse strains. However, their roles in human disease within the ‘real world’ of diverse genetic backgrounds, natural infection and environmental challenges remains less well understood. Over 20 unique disease-associated human germline gene variants in this core necroptotic machinery have been reported in the literature and human clinico-genetics databases like ClinVar to date. In this review, we provide an overview of these human gene variants, with an emphasis on those encoding MLKL. These experiments of nature have the potential to not only enrich our understanding of the basic biology of necroptosis, but offer important population level insights into which clinical indications stand to benefit most from necroptosis-targeted drugs.

A common humanMLKLpolymorphism confers resistance to negative regulation by phosphorylation

“…Consistent with this notion, more than 20 unique disease-associated human germline gene variants in the core necroptotic machinery, encompassing RIPK1, RIPK3, MLKL, have been identified (Garnish and Hildebrand, 2022;Zhang et al, 2021). In one family, a haplotype including a rare MLKL loss-of-function gene variant (p.Asp369GlufsTer22, rs561839347) is associated with a severe and progressive novel neurogenerative spectrum disorder characterized by global brain atrophy (Faergeman et al, 2020).…”

Mediators of necroptosis: from cell death to metabolic regulation

“…While these cases are rare, they hold the potential to provide valuable insights into the role of MLKL in disease etiology. They may contribute to a more focused and refined study of the trait- and disease-modifying potential of MLKL protein-coding variants carried by over 10% of the global population (Garnish and Hildebrand, 2022 ), leading to the identification of new clinical indications and contraindications for drugs targeting necroptosis and its upstream regulators. Such investigations will shed further light on whether the absence of MLKL alone is sufficient to affect metabolic disease or if other genetic or environmental factors are also involved in disease development.…”

A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation

“…Consistent with this notion, more than 20 unique disease-associated human germline gene variants in the core necroptotic machinery, encompassing RIPK1, RIPK3, MLKL , have been identified 34 , 35 . In one family, a haplotype including a rare MLKL loss-of-function gene variant ( p.Asp369GlufsTer22 , rs561839347) is associated with a severe and progressive novel neurogenerative spectrum disorder characterized by global brain atrophy 36 .…”